Targeting Blood Vessels That Keep Cancer Alive

By

Researchers from at the University of Pennsylvania are using a DNA vaccine to kill cancer, not by attacking tumor cells but targeting the blood vessels that keep them alive. The vaccine also indirectly creates an immune response to the tumor itself, which amplifies the attack because of a phenomenon called epitope spreading. The results of the study were published in April 2014 in the Journal of Clinical Investigation.

A release from the university explains that previous studies have targeted tumor angiogenesis, which is the formation of new blood vessels that feed the tumor cells. However, this approach can also interfere with normal processes involved in wound healing. Penn researchers avoided this pitfall by designing a DNA vaccine that specifically targets TEM1 (tumor endothelial marker 1), a protein that is overexpressed in tumors and poorly expressed in normal tissues.

The release quotes Andrea Facciabene PhD as saying, “We demonstrated that by targeting TEM1, our vaccine can decrease tumor vascularization, increase hypoxia of the tumor and reduce tumor growth. Our results confirm that we were directly targeting the tumor vasculature and also indirectly killing tumor cells through epitope spreading.”

The Penn team injected mice with a DNA fusion vaccine called TEM1-TT, created by fusing TEM1 complementary DNA with a fragment of the tetanus toxoid (TT). In mouse models of three cancer types (breast, colon, and cervical), tumor formation was delayed or prevented in mice vaccinated with the TEM1-TT DNA vaccine. Specifically, the team found that the mouse tumors had suppressed growth, decreased tumor vessel formation, and increased infiltration of immune cells into tumors.

"Until now there have been a lot of clinical trials using DNA vaccines to target tumors themselves, but unfortunately the results have been disappointing," Facciabene notes. "This is a different approach which should heighten optimism for cancer vaccines in general. Moreover, based on what we’ve seen in our mouse studies, this vaccine doesn’t seem to show any significant side effects."

The prevalence of TEM1 in a wide range of tumor types coupled with its scarcity in normal vessels makes it a suitable target both for a prophylactic defense against cancer and a complement to other therapies such as radiotherapy and chemotherapy. "Using this vaccine simultaneously with radiation may eventually have a double synergy," Facciabene says. "Both treatments affect the tumor endothelium, radiotherapy could help the phenomenon of epitope spreading induced by the TEM1-TT vaccine." In addition to ongoing pre-clinical work with human TEM1, Facciabene and colleagues are planning to move on to Phase I human clinical trials.

The authors suggest that TEM1 may also be an excellent target as a prophylactic cancer vaccine for individuals that have a high risk of developing ovarian cancer, such as carriers of the BRCA1/2 mutations, predominant in breast and ovarian cancer. Research to develop those types of strategies is a key goal of Penn’s Basser Research Center for BRCA. As a bonafide vaccine, TEM-TT DNA vaccine generates a memory immune response, which Facciabene says is an ideal attribute for high risk populations.